Benzimidazole derivatives as ERBB tyrosine kinase inhibitors for the treatment of cancer

Abstract

Provided herein are benzimidazole derivatives, for example, of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a proliferative disease.

What is claimed is: 
     
       1. A compound of Formula VI: 
       
         
           
           
               
               
           
         
         or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; 
         wherein R 1  is -C(O)CH═CHR 1f , wherein R 1f  is hydrogen, dimethylaminomethyl, pyrrolidin-1-ylmethyl, or piperidin-1-ylmethyl; or R 1  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R 2  is C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; 
         R 4 , R 5 , R 6 , and R 7  are each independently (a) hydrogen, cyano, halo, or nitro; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c ,—NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; with proviso that at least two of R 4 , R 5 , R 6 , and R 7  are not hydrogen; and with the proviso that R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  are linked together to form heteroaryl or heterocyclyl; 
         each R 1a , R 1b  and R ic  is independently hydrogen, C 1-6 alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or R 1a  and R 1c  together with the C and N atoms to which they are attached form heterocyclyl; or R 1b  and R 1c  together with the N atom to which they are attached form heterocyclyl; and 
         wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, and is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , -OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OP(O)(OR a ) 2 , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d  is independently (i) hydrogen; (ii) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; or (iii) R b  and R c  together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q a ; 
         wherein each Q a  is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-5  aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R f , —C(O)OR f , —C(O)NR g R h , —C(NR f )NR g R h , —OR f , —OC(O)R f , —OC(O)OR f , —OC(O)NR g R h , —OC(═NR f )NR g R h , —OP(O)(OR f ) 2,  —OS(O)R f , —OS(O) 2 R f , —OS(O)NR g R h , —OS(O) 2 NR g R h , —NR g R h , —NR f C(O)R k , —NR f C(O)OR k , —NR f C(O)NR g R h , —NR f C(═NR k )NR g R h , —NR f S(O)R k , —NR f S(O) 2 R k , —NR f S(O)NR g R h , —NR f S(O) 2 NR g R h , —SR f , —S(O)R f , —S(O) 2 R f , —S(O)NR g R h , and —S(O) 2 NR g R h ; wherein each R f , R g , R h , and R k  is independently (i) hydrogen; (ii) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or (iii) R g  and R h  together with the N atom to which they are attached form heterocyclyl. 
       
     
     
       2. The compound, or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , wherein R 1  is —C(O)CH═CHR 1f , wherein R 1f  is hydrogen, demethylaminomethyl, pyrrolidin-1-ylmethyl, or piperidin-1-ylmethyl. 
     
     
       3. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       4. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , wherein R 2  is C 6-14  aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more sub stituents Q. 
     
     
       5. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 4 , wherein R 2  is 6- to 10-membered monocyclic or bicyclic aryl, optionally substituted with one or more substituents Q. 
     
     
       6. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 4 , wherein R 2  is 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents Q. 
     
     
       7. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 4 , wherein R 2  is phenyl, pyridinyl, pyridazinyl, benzo[c][1,2,5]oxodiazolyl, or benzo[c][1,2,5]thiodiazolyl, each of which is optionally substituted with one or more substituents Q. 
     
     
       8. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , wherein R 4  is hydrogen. 
     
     
       9. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , wherein R 5  and R 6  are linked together to form heterocyclyl, optionally substituted with one or more sub stituents Q. 
     
     
       10. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 9 , wherein R 5  and R 6  are linked together to form heterocyclyl selected from: 
       
         
           
           
               
               
           
         
       
     
     
       11. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , wherein R 7  is hydrogen. 
     
     
       12. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , wherein R 7  is chloro, methyl, or methoxy. 
     
     
       13. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , wherein R 6  and R 7  are linked together to form heterocyclyl, optionally substituted with one or more substituents Q. 
     
     
       14. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 13 , wherein R 6  and R 7  are linked together to form heterocyclyl selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein p is an integer of 1, 2, 3, 4, 5, or 6. 
       
     
     
       15. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , wherein R 5  is hydrogen. 
     
     
       16. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         . 
       
     
     
       17. The compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         . 
       
     
     
       18. A pharmaceutical composition comprising the compound or single enantiomer, racemic mixture, mixture of diastereomers, isotopic variant, pharmaceutically acceptable salt, solvate, or prodrug thereof of  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
       19. The pharmaceutical composition of  claim 18 , wherein the composition is formulated for oral, nasal, bronchial, or topical administration. 
     
     
       20. The pharmaceutical composition of  claim 18 , wherein the composition is formulated as a single dosage form.